Genome-wide association studies (GWAS) have recently identified a region of chromosome 9p21 as the most important source of heritable cardiovascular risk. This locus is independent of traditional risk factors such as smoking, hypertension and hyperlipidemia, suggesting it potentiates disease via a novel mechanism. The most predictive 9p21 variants account for more than 20% of an individual's lifetime risk for coronary artery disease. Despite being implicated in the leading cause of death in the Western world, the mechanism(s) by which these polymorphisms lead to vascular disease remain unclear. In this proposal, the investigators seek to elucidate the relationship between a leading candidate gene at the 9p21 risk locus, CDKN2B, and vascular disease. Specifically, they will query the role of this gene in angiogenesis, and the concept that CDKN2B may regulate disease via a paradoxical and antagonistic effect on blood vessel sprouting, and blood vessel maturation. This proposal will bring together recognized experts from several fields, deeply phenotyped human tissue samples and unique mouse models with the objective of fully describing the vascular biology of CDKN2B. This application includes three specific aims which will: 1) Map the molecular mechanism by which CDKN2B regulates blood vessel stabilization; 2) Employ novel cell-specific Cdkn2b knockout animals to specifically determine which cell type regulates the pathologic response to ischemia, and whether the process is reversible; and 3) Determine whether the angiogenic defect also promotes atherosclerotic plaque vulnerability and myocardial infarction in human carriers of the 9p21 risk allele. The objective of these studies is to 'reverse translate' the biology of the 9p21 locus and contribute to the field of cardiovascular genetics in the post-GWAS era. Discoveries made in the course of this proposal are intended to support the stated mission of the National Institutes of Health and provide contributions that will lead to the development of new translational therapies for patients with cardiovascular disease.